Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance

发现和利用神经母细胞瘤治疗耐药的机制

• 批准号: 9359221
• 负责人: JOHN M MARIS
• 金额: $ 229.69万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9359221
• 关键词: Address; Adolescent; Adult; Agreement; Antibodies; Automobile Driving; Biological Markers; Biometry; Biostatistics Core; Cancer Burden; Cancer Etiology; Cell model; Cessation of life; Child; Child Care; Clinical Trials; Collaborations; Collection; Combined Modality Therapy; Complex; Coupled; Data; Development; Disease; Ecosystem; Engineering; Epigenetic Process; Evolution; Genetic; Genomics; Goals; Health; Heterogeneity; Human; Immune; Immune Evasion; Immunooncology; Immunotherapy; In Vitro; Intervention; Leadership; Malignant Childhood Neoplasm; Malignant Neoplasms; Methodology; Mission; Modeling; Modernization; Molecular; Morbidity - disease rate; Motivation; Neuroblastoma; Oncogenic; Patient-Focused Outcomes; Patients; Pediatric Oncology Group; Phase; Physicians; Play; Pre-Clinical Model; Probability; Program Research Project Grants; Public Health; Publishing; Recurrent disease; Refractory; Relapse; Research; Research Design; Research Personnel; Research Support; Resistance; Resources; Role; Sampling; Services; Solid; Sympathetic Nervous System; Testing; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; Time; Translating; Translations; Treatment Failure; United States National Institutes of Health; Work; Xenograft procedure; anticancer research; base; cancer therapy; chemoradiation; chemotherapy; clinical predictors; clinical translation; clinically relevant; design; evidence base; experience; experimental study; high risk; improved; improved outcome; innovation; insight; molecular targeted therapies; mouse model; multidisciplinary; neoplastic cell; new therapeutic target; novel; novel marker; novel strategies; novel therapeutics; patient population; pre-clinical; preclinical trial; pressure; programs; resistance mechanism; response; small molecule therapeutics; success; targeted treatment; therapeutic candidate; therapy resistant; translational research program; tumor; tumor microenvironment; tumorigenesis

SUMMARY/ABSTRACT The field of childhood cancer research is at a crossroads. After stunning improvements, cure rates for most pediatric malignancies have plateaued. Indeed, children with metastatic solid malignancies continue to have less than a 50% chance of survival despite being treated with highly intensive chemoradiotherapy. Neuroblastoma (NB), a diverse malignancy arising from the developing sympathetic nervous system, is an outstanding model for the problem of childhood cancer in general and is the focus of this new Program Project Grant. The primary goal of this multi-institutional and multi-disciplinary Program is to achieve improved outcomes for patients with high-risk, disseminated NB by: 1) discovering basic mechanisms of resistance to modern therapies; 2) uncovering targetable vulnerabilities driving resistance; and 3) translating these insights into evidence-based clinical trials. The five proposed Projects focus on interrelated fundamental problems in the broad fields of genomics (Projects 1 and 2), epigenetics (Project 3), tumor microenvironment (all Projects) and immuno-oncology (Projects 1, 2, 4 and 5). The central hypothesis is that high-risk NBs evolve to evade therapeutic interventions but that these resistance mechanisms can be targeted therapeutically. The motivation for the proposed research is the urgent need to improve survival of patients with high-risk NB, and to decrease treatment-related morbidities. The five proposed Projects will each address three Specific Aims of the overall Program: 1) discover mechanisms of NB therapy resistance; 2) discover tumor-intrinsic and tumor- extrinsic therapeutic vulnerabilities imparted by therapy resistance; and 3) develop readily translatable therapeutic strategies to exploit de novo and acquired resistance mechanisms and molecular vulnerabilities. The Projects will each be supported by three Cores: A) Research Support Services; B) Clinical Trials and Translation; and C) Biostatistics. Unique to the Program is a mature clinical trials consortium integrated into Core B (New Approaches to NB Therapy [NANT] consortium). Critical to the success of each Project is unparalleled access to therapy resistant tumors from the NANT, and sharing of clinically relevant in vitro and murine models. Importantly, all Projects have clear milestones to deliver one or more clinical trials to the NANT, with Project specific studies designed to provide a portfolio of nonclinical data required for efficient translation to the refractory NB patient population. This highly integrated Program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, kinome reprogramming, epigenetic adaptation and immune evasion, but is steadfastly translational, as the investigative team is constituted with physicians who care for children with this disease. The significance of the proposed program is the likely discovery of fundamental mechanisms of cancer therapy resistance leading to substantively improved probability of cure coupled with reduced therapy-related morbidity for children, adolescents and adults afflicted with high-risk NB.

摘要/摘要 儿童癌症研究领域处于十字路口。经过惊人的改进，大多数 小儿恶性肿瘤已稳定下来。确实，具有转移性固体恶性肿瘤的儿童继续存在 尽管接受了高度强化的化学放疗治疗，但生存的机会不到50％。 神经母细胞瘤（NB）是由发展的交感神经系统引起的多种恶性肿瘤，是一种 一般来说，儿童癌症问题的杰出模型是这个新计划项目的重点 授予。这个多机构和多学科计划的主要目标是提高 高风险，传播NB的患者的结果：1）发现抗药性的基本机制 现代疗法； 2）发现驱动阻力的目标漏洞； 3）翻译这些见解 进入循证临床试验。五个拟议的项目着重于相互关联的基本问题 基因组学的广泛领域（项目1和2），表观遗传学（项目3），肿瘤微环境（所有项目） 和免疫肿瘤学（项目1、2、4和5）。中心假设是高风险NBS演变为逃避 治疗性干预措施，但这些耐药机制可以治疗。这 拟议研究的动机是迫切需要改善高风险NB患者的生存，并需要 减少与治疗相关的病态。五个拟议的项目将针对三个特定目标 总体计划：1）发现NB治疗抗性的机制； 2）发现肿瘤内在和肿瘤 通过耐药性赋予的外部治疗脆弱性； 3）很容易翻译 利用从头并获得抗药性机制和分子脆弱性的治疗策略。 这些项目将由三个核心支持：a）研究支持服务； b）临床试验和 翻译;和c）生物统计学。该计划独有的是一个成熟的临床试验财团集成到 Core B（NB治疗[NANT]财团的新方法）。每个项目的成功至关重要 从NANT获得抗治疗肿瘤的无与伦比，并共享体外临床相关的和 鼠模型。重要的是，所有项目都有明确的里程碑，可以向 Nant，旨在提供有效效率所需的非临床数据组合的项目组合 转化为难治性NB患者人群。这个高度集成的程序提出了各种各样的 创新的实验策略，以发现肿瘤发生的基本机制，Kinome重新编程， 表观遗传适应和免疫逃避，但由于调查团队是 由关心这种疾病儿童的医生组成。拟议程序的意义 是否可能发现癌症治疗抗性的基本机制，从而实质上 改善治愈的可能性，以及减少儿童，青少年和治疗相关的发病率 成年人患有高危NB。